Molecular mechanism for the regulation of septic shock by endogenous antimicrobial cathelicidin peptides

多肽抗生素对入侵的微生物具有很强的抗菌活性，有助于天然的宿主防御。作为一种抗菌素，人IL-37和人B-防御素(HBDS)不仅具有很强的杀菌活性，而且对包括中性粒细胞在内的免疫细胞具有趋化作用。在包括败血症在内的细菌感染过程中，中性粒细胞的寿命受到各种病原体和宿主衍生物质的调节。在这里，为了进一步评估IL-37和hBDS在先天免疫中的作用，我们研究了它们对中性粒细胞凋亡的作用。根据形态变化，使用人血中性粒细胞来评估中性粒细胞的凋亡。值得注意的是，IL-37和HBD-3可抑制中性粒细胞的凋亡，同时伴有ERK-1/-2的磷酸化、抗凋亡蛋白Bclxl的表达和caspase3活性的抑制。有趣的是，IL-37和HBD-3诱导的中性粒细胞凋亡抑制分别被甲酰肽受体样1(FPRL1)和P2X7核苷酸受体拮抗剂以及趋化因子受体CCR6减弱。这些观察结果表明，在细菌感染中，LL-37和HBD-3不仅可以杀死细菌，而且可以通过激活FPRL1、P2X7和CCR6来调节(抑制)中性粒细胞凋亡。抑制中性粒细胞的凋亡可延长其寿命，可能有利于宿主抵御细菌入侵。然而，中性粒细胞凋亡的抑制可能导致细胞毒性代谢产物和促炎物质(即活性氧和蛋白酶)的不受控制的释放，从而导致全身炎症、组织损伤和器官衰竭的放大。

Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. An antibacterial cathelicidin, human LL-37 and hBDs (human B-defensins) not only exhibits potent bactericidal activities but also functions as a chemoattractant for immune cells including neutrophils. During bacterial infections including sepsis, the lifespan of neutrophils is regulated by various pathogen and host-derived substances. Here, to further evaluate the role of LL-37 and hBDs in innate immunity, we investigated their actions on neutrophil apoptosis.Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, LL-37 and HBD-3 suppressed neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/-2, expression of Bcl-XL (an anti-apoptotic protein) and inhibition of caspase 3 activity. Interestingly, LL-37- and hBD-3-induced suppression of neutrophil apoptosis was attenuated by the antagonists for formyl-peptide receptor-like 1 (FPRL1) and P2X7 nucleotide receptor, and a chemokine receptor CCR6, respectively.Collectively, these observations indicate that LL-37 and hBD-3 can not only kill bacteria but also modulate (suppress) neutrophil apoptosis via the activation of FPRL1 and P2X7, and CCR6, respectively, in bacterial infections. Suppression of neutrophil apoptosis results in the prolongation of their life span and may be advantageous for host defense against bacterial invasion. However, the suppressed neutrophil apoptosis may causes the uncontrolled release of cytotoxic metabolites and pro-inflammatory substances (i.e. reactive oxygen species and proteases), which leads to the amplification of systemic inflammation, tissue injury and organ failure observed in sepsis.